Scalable ruthenium-catalyzed asymmetric synthesis of a key intermediate for the β2-adrenergic receptor agonist

Article abstract of DOI:10.1021/op500338d

An enantioselective and robust synthetic process to obtain a useful intermediate for the β2-adrenergic receptor agonist is described. Asymmetric transfer hydrogenation of ketone 1c by (S,S)-3b (Ms-DENEB) afforded chiral alcohol 2c in 71% isolated yield and 99% ee. The deprotection completed the synthesis of (R)-5 in 41% overall yield from 1b, which is readily commercially available.

Full text of DOI:10.1021/op500338d

Communication
pubs.acs.org/OPRD
Scalable Ruthenium-Catalyzed Asymmetric Synthesis of a Key
Intermediate for the β2-Adrenergic Receptor Agonist
Masato Komiyama,* Takahiro Itoh, and Takumi Takeyasu
Process Technology Group, Pharmaceutical Production & Technology Department, Teijin Pharma Limited, Tokyo 191-8512, Japan
S
* Supporting Information
Scheme 1. Reported synthetic approach
ABSTRACT: An enantioselective and robust synthetic
process to obtain a useful intermediate for the β2-
adrenergic receptor agonist is described. Asymmetric
transfer hydrogenation of ketone 1c by (S,S)-3b (Ms-
DENEB) afforded chiral alcohol 2c in 71% isolated yield
and 99% ee. The deprotection completed the synthesis of
(R)-5 in 41% overall yield from 1b, which is readily
commercially available.
reported. The CBS method is the most widely applied
procedure and affords excellent results for a wide range of
ketone substrates. Theravance Inc. has reported the use of CBS
reduction to prepare several biphenyl derivatives with β2-
adrenergic receptor agonist and muscarinic receptor antagonist
activity.7 GSK961081 has been prepared by CBS reduction of
ketone.8
espiratory diseases such as asthma and chronic obstructive
R
pulmonary disorder (COPD) are highly prevalent and
affect millions of people all over the world.1 Indacaterol,
abediterol, and carmoterol, the most common β2-adrenergic
receptor (adrenoreceptor) agonist inhalers, exhibit modest
biological activity (Figure 1).2 Several research programs dealt
Ru-catalyzed asymmetric transfer hydrogenation (ATH) of a
ketone has been reported for the preparation of indacaterol and
abediterol.9 The synthetic method for carmoterol was based on
reduction using NaBH4 as a reducing agent via internal
asymmetric induction.10 These methods can be developed to
prepare useful compounds in excellent yields, but the key
asymmetric reduction methods are impractical for manufactur-
ing. In the development of our drug candidates, we wished to
avoid using a stoichiometric boron reagent. In addition, due to
the limited availability of some substrates, we did not want the
progress of the reaction to be limited by the substrate, which
has a moiety essential for biological activity.11 Consequently,
we developed an alternative synthetic route to improve the
synthesis of the intermediate in terms of safety, environmental
friendliness, and robustness. Herein we report a novel efficient
synthesis of key intermediate 2 via Ru-catalyzed ATH of ketone
1.12
Figure 1. β-Amino-α-hydroxyquinolinones.
Recently, Takasago International Corporation developed
new oxo-tethered ruthenium amide complexes, including
DENEB.13 This catalyst exhibited excellent catalytic perform-
ance for both ATH and H2 hydrogenation of acetophenone
derivatives without any cocatalysts to give chiral secondary
alcohols with high levels of enantioselectivity. In conjunction
with the development of our drug candidates, we applied a
novel Ru-catalyzed ATH reaction to ketone 1 to produce the
chiral alcohol 2.
with the modification of quinolinone derivatives.3 This led to
the synthesis of several highly biologically active derivatives,
including GSK961081, a combination of a β2-adrenergic
receptor and a muscarinic receptor antagonist.4 Chiral β-
amino-α-hydroxyquinolinone moieties are essential for bio-
logical activity, and we synthesized a series of quinolinone
analogues with the same functionalities with the aim of
developing drug candidates.
A previous synthesis of a series of hydroxyquinolinones (2)
was adopted in part from that of ketone 1 by asymmetric
reduction (Scheme 1). Asymmetric reductions of ketone
intermediates 1, including Corey−Bakshi−Shibata (CBS)
reduction5 and Ru-catalyzed hydrogenation,6 have been
In the initial study, we carried out ATH of α-chloroketone 1a
with tethered complex (R,R)-3a (Ts-DENEB) in a mixture of
Received: October 28, 2014
© XXXX American Chemical Society
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HCO2H/NEt3 to give the corresponding chiral alcohol 2a,
which could be transformed to various compounds (Scheme 2).
easy deprotection at the subsequent step. The Cbz group can
be removed by typical hydrogenation under mild conditions to
prevent reduction of the quinolinone double bond. Hydro-
genation of the N-Bn moiety instead of Cbz gave a troublesome
byproduct via olefin reduction.16 Asymmetric reduction of 1c
with (R,R)-3a proceeded to afford (S)-2c in quantitative yield,
but the ee was lower than that obtained using Ms-DENEB
(entry 8). The reduction reactions were carried out at lower
temperatures to achieve slightly better enantioselectivity, but
the reaction time was longer in each case (entries 9 and 10).
However, the use of the typical catalyst (S,S)-3c (RuCl-
(TsDPEN(p-cymene))6c gave the product 2c with very low
conversion (entry 11). As a further investigation, the influence
of the solvent on the ATH of ketone 1c was studied.17
However, no activity was measured when the reaction
proceeded in alcohol-like IPA, which also acts as a proton
donor and accelerates product release from the reaction
intermediate. Among several compounds investigated, the
transfer hydrogenation of ketone 1c without any cosolvent
was improved in terms of chemical yield and enantioselectivity
by using (R,R)-3a in the presence of a high concentration of
hydrogen donor (entry 12). Finally, asymmetric reduction with
(S,S)-3b gave the corresponding desired chiral alcohol (R)-2c
in quantitative chemical yield with high enantio purity (entry
13). Incidentally, the reduced olefin byproduct was not
observed under the ATH conditions by LC-MS analysis. We
also managed to avoid using CHCl3, which is not an
environmentally friendly solvent.
Scheme 2. ATH of ketones
After screening several cosolvents,14 we found that CHCl3
led to complete conversion after 2 h at 50 °C, giving the chiral
alcohol 2a in good yield with moderate to good ee (Table 1,
Table 1. ATH of ketones catalyzed by (R,R)-3a, (S,S)-3b, or
a
(S,S)-3c
b
entry ketone cat. temp (°C) time (h) HPLC area %
% ee
From the point of view of enantioselectivity, a promising
result was obtained with the oxo-tethered ruthenium amide
complex (S,S)-3b in comparison with (R,R)-3a. As reported by
Takasago group, the Ms-analogue provided a better result than
the Ts-analogue in view of the ATH enantioselectivity of 1-
acetophenone derivatives.13 Our results support the conclusion
that the oxo-tethered ruthenium complex shows remarkable
catalytic performance for both ATH and hydrogenation of
ketones. As reported by Wills’s group,18 the structure of the
substrate might also influence enantioselectivity due to both the
arene/aryl interaction and potential repulsive interaction. ATH
of the Cbz moiety of 1c takes place through a transition state
via the well-established arene/aryl interaction, preventing steric
interactions (Figure 2).
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
3a
3b
3a
3b
3b
3b
3b
3a
3a
3b
3c
3a
3b
50
50
50
50
25
25
50
50
25
25
25
50
50
2
2
94
94
36
56
67
94
99
99
99
99
53
98
99
70 (S)
90 (R)
75 (S)
92 (R)
95 (R)
94 (R)
92 (R)
69 (S)
75 (S)
95 (R)
90 (R)
83 (S)
95 (R)
2
2
24
24
2
c
2
24
24
24
26
6
10
11
12
13
d
d
a
Standard reaction conditions: ruthenium catalyst (1 mol %), 2 M
HCO2H/NEt3 (5:2), and 0.5 M CHCl3. The ee was determined by
b
HPLC analysis using DAICEL CHIRALPAK AS-RH, 5 μm, 4.6 × 150
c
mm column. 10 equiv of HCO2K and 5 equiv of HCO2H in place of
d
HCO2H/NEt3. 0.25 M HCO2H/NEt3 (5:2) without 0.5 M CHCl3,
entries 1 and 2). ATH using the more bulky substrate 1b gave
miserable yields, but the enantioselectivity was slightly better
than for 1a (entries 3 and 4). In those cases, reduction of the
ketone proceeded with the SN2 substitution on the bromo
functional group with HCO2H, giving a large amount of
nucleophilic substitution compounds as major side products.15
The yield did not change dramatically upon decreasing the
reaction temperature (entry 5). To prevent nucleophilic
substitution, HCO2K was used as an insoluble salt, which
improved the yield dramatically (entry 6), but it was difficult to
avoid nucleophilic substitution of the substrate 1b. Con-
sequently, asymmetric reduction of N-protected α-amino
ketone 1c was conducted using (S,S)-3b (Ms-DENEB) at 50
°C for 2 h to afford the corresponding (R)-2c in high yield with
92% ee as the desired configuration (entry 7). The Cbz group is
a much more practical protecting group for amine in terms of
Figure 2. Predicted reduction of ketone 1c.
As indicated in Table 1, a highly enantiopure product, (R)-
2c, was obtained, but the enantiopurity (95% ee) was not
sufficient for our drug candidate study. Therefore, we have
developed an efficient method for achieving an improvement in
enantiopurity (>99% ee). Among the compounds tested, we
found that the addition of i-PrOH to the reaction mixture
directly as an antisolvent gave the desired product (R)-2c in
73% isolated yield with >99 area% and 99% ee at a relatively
low catalyst concentration (Scheme 3). This process is concise
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preparation of various analogues of (R)-5 on a multikilogram
scale.
Scheme 3. Improvement of enantiopurity by crystallization
EXPERIMENTAL SECTION
■
General Information. All reaction carried out under
nitrogen. Asymmetric transfer hydrogenation generates CO2
gas, so the reactor should be vented. Melting points (m.p.)
were measured using a Yanaco MP-S3 melting point apparatus
1
and are uncorrected. H and 13C NMR spectra were recorded
on JEOL JNM-AL-400 (400 and 100 MHz) as noted. Data for
1H NMR are reported as follows: chemical shift (δ ppm),
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, m =
multiplet), coupling constant (Hz), integrationm and major or
minor of rotamers. Optical rotations were obtained using
JASCO P-1020 with a 1 mL cell and a 0.1 dm path length. Data
for 13C NMR are reported in terms of chemical shift. IR spectra
were obtained from Tharmo Nicolet AVATAR 320. High-
resolution mass spectra were obtained from SHIMADZU
LCMS-IT-TOF. Data for residual ruthenium were recorded on
Rigaku EDXL300.
and straightforward for manufacturing operations. Interestingly,
the enantiopurity of the mother liquor was much higher than
that of the solid when alternative antisolvents such as
acetonitrile, dichloromethane, and EtOAc were used (see
Supporting Information).
A high-yielding synthesis of the N-Cbz-protected ketone 1c
from the commercially available compound 1b via amidation
and Cbz protection was developed (Scheme 4). With
Scheme 4. Synthesis of key intermediate (R)-5
General Procedure of Asymmetric Transfer Hydro-
genation. Entries 1−5 and 7−11. To compound 1a, 1b, or 1c
(200 mg) and ruthenium catalyst (1 mol %) were added CHCl3
(0.5 M), HCO2H/TEA (5:2, 2 M) under N2 atmosphere. The
resulting slurry was agitated at any temperature.
Entries 6. To compound 1b (200 mg, 0.537 mmol), (S,S)-3b
(3.1 mg, 0.0054 mmol)m and HCO2K (452 mg, 5.37 mmol)
were added CHCl3 (1.07 mL) and HCO2H (124 mg, 2.69
mmol) under N2 atmosphere. The resulting slurry was agitated
at 25 °C for 24 h.
Entries 12, 13. To compound 1c (200 mg, 0.452 mmol) and
(R,R)-3a (S,S)-3b (0.0045 mmol) was added HCO2H/TEA
(5:2, 1.81 mL) under N2 atmosphere. The resulting slurry was
agitated at 50 °C.
compound 1c in hand, we proceeded with ATH to give the
desired chiral alcohol 2c in good isolated yield with high ee.
The results were consistent with previous lab-scale trials, and
these process conditions were successfully demonstrated in a
reproducible manner to give the product on a multikilogram
scale. The chiral secondary alcohol of 2c was protected by a
TBS group, which allowed easy deprotection. The resulting
TBS-protected product, without further isolation, was treated
under hydrogenation conditions, involving simultaneous
deprotection of the N-Cbz and O-Bn groups. Preliminary
results showed that reduction by hydride methods using
hydrogen gave unsatisfactory selectivity, with reduction of the
double bond of the quinolinone moiety.19 Among the various
conditions examined, transfer hydrogenation with Pd/C/
HCO2K gave the product 5 with manageable levels of the
side product. After aqueous workup, the desired (R)-5 was
isolated as an acetate salt in 83% yield, with >99% purity and
>99% ee by the addition of AcOH to the organic layer.20
Downgrading of the enantiopurity of 2c did not occur in
subsequent steps under the conditions used. The resulting
chiral alcohol (R)-5 was converted to several drug candidates.21
In conclusion, an efficient and scalable enantioselective
synthesis of the intermediate (R)-5 for a β2-adrenergic receptor
agonist has been developed. This synthesis features an
enantioselective reduction of α-amino-1-acetophenone deriva-
tive 1c using the novel chiral ruthenium catalyst Ms-DENEB.
Effective transfer hydrogenation of the chiral alcohol afforded
the primary amine (R)-5 in >99% ee. Starting from the
commercially available quinolinone derivative 1b, the key
scaffold of β2-adrenergic receptor agonists was prepared in 41%
yield over four steps. This synthetic method is applicable to the
Preparation of 5-(2-Aminoacetyl)-8-(benzyloxy)-1,2-dihy-
droquinolin-2-one Hydrochloric Acid Salt (4). To a 300 L
glass lined vessel was added 8-(benzyloxy)-5-(2-bromoacetyl)-
1,2-dihydroquinolin-2-one (1b, 8.43 kg, 22.6 mol), NaN-
(CHO)2 (2.77 kg, 28.3 mol), and acetonitlile (66.3 kg) under
N2 atmosphere. The resulting slurry was warmed to 65 °C for
50 min and agitated at 65−68 °C for 10 h until >99.0%
conversion was achieved by HPLC. The batch was allowed to
cool to 10 °C for 10 h. To the resulting slurry was added THF
(75.6 kg) and 6 N HCl (18.4 kg) under N2 atmosphere. The
resulting slurry was warmed to 65 °C for 70 min and stirred at
65−68 °C for 6 h until >99.0% conversion was achieved
according to HPLC analysis (refer to the HPLC method in the
Supporting Information). The batch was allowed to cool to 23
°C for 15 h and then cooled to 5 °C for 55 min. After aging at
0−5 °C for 1 h, the solid was collected by filtration. The wet
cake of compound 4 was washed with THF (60.0 kg) and
obtained as a white solid (9.80 kg).
A sample of compound 4 was purified for NMR analysis by
recrystallization from EtOH/H2O. The purified compound 4
gave the NMR data as follows. 1H NMR (DMSO, 400 MHz): δ
= 11.15 (br s, 1H), 8.71 (d, J = 10.2 Hz, 1H), 8.30 (br s, 3H),
7.87 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 6.8 Hz, 2H), 7.38 (t, J =
7.3 Hz, 2H), 7.35−7.29 (m, 2H), 6.72 (d, J = 10.2 Hz, 1H),
5.45 (s, 2H), 4.54 (s, 2H). 13C NMR (DMSO, 100 MHz): δ =
193.8, 160.6, 148.3, 137.1, 135.9, 130.3, 128.4, 128.1, 127.9,
126.6, 124.8, 123.0, 117.5, 110.8, 70.1, 45.6; HRMS calculated
for C18H17N2O3 (M + H): 309.1234, found: 309.1227. The
melting point is 222 °C (degradation).
C
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22
Preparation of Benzyl N-{2-[8-(benzyloxy)-2-oxo-1,2-dihy-
droquinolin-5-yl]-2-oxoethyl} Carbamate (1c). To a 600 L
glass-lined vessel was added wet compound 4 (9.80 kg, <22.6
mol) and THF (59.8 kg) under N2 atmosphere. To the slurry
was added CbzCl (4.25 kg) at 4 °C for 2 min, and the resulting
mixture was aged at 0−4 °C for 30 min. The solution of DIPEA
(7.33 kg) and THF (8.82 kg) was charged over 75 min at 0−3
°C. The resulting slurry was stirred at 2−5 °C for 40 min until
the reaction was deemed complete (Refer to HPLC method in
Supporting Information). The reaction was quenched by
addition of the solution of methanol (30.0 kg) and deionized
water (37.8 kg) at 2−10 °C for 35 min. The resulting slurry was
stirred at 6−10 °C for 18.5 h followed by stirring at −4 to 3 °C
for 1 h. The solid was collected by filtration and washed with
the solution of methanol (30.0 kg) and ion-exchanged water
(37.8 kg) followed by methanol (46.5 kg). Drying in vacuum at
50 °C afforded compound 1c as a white solid (6.99 kg, 69.7%
from 4, 99.7% purity).
[α]D = +18.4 (c = 2.10, DMSO)
Improvement Enantiopurity of Compound 2c in Filtrate
from the Mother Liquor and Isolation of Racemate. IPA was
evaporated from 800 mL of the mother liquor of 2c under
reduced vacuum pressure. To the resulting solution (148 g,
83% ee) was added EtOAc (200 mL) and stirred for 30 h at
room temperature. The resulting slurry was stirred in ice bath
for 4 h. The solid was collected by filtration and washed with
the solution of EtOAc (15 mL) and heptane (15 mL) followed
by cooled EtOAc (40 mL). The collected compound racemic-
2c as a white solid (1.46 g, 3.5%, 0.82% ee), and the enantio
purity in the mother liquor was higher than the original (95.5%
ee). The melting point is 168 °C.
P r e p a r a t i o n o f 5 - [ ( 1 R ) - 2 - A m i n o - 1 - [ ( t e r t -
butyldimethylsilyl)oxy]ethyl]-8-hydroxy-1,2-dihydroquinolin-
2-one diacetic acid salts ((R)-5). To a 600L glass lined vessel
was added compound 2c (5.00 kg, 11.3 mol), Imidazole (1.55
kg, 22.8 mol), DMF (23.6 kg) and iPrOAc (11.0 kg) under N2
atmosphere. To the solution was added 50 wt % TBSCl in
EtOAc (6.78 kg, 22.6 mol) at 9−15 °C for 5 min. The solution
heated to 75 °C for 33 min and aged at 75−82 °C for 4 h until
>99.0% conversion was achieved according to HPLC analysis
(refer to HPLC method in the Supporting Information). The
batch was cooled to 9 °C and quenched by addition of
deionized water (25.0 kg) and iPrOAc (22.0 kg) at 9−17 °C.
The organic layer containing TBS protected compound 2c was
separated and washed twice with deionized water (25.0 kg +
25.0 kg). The organic layer was allowed to remain for 18 h
under N2 atmosphere below 17 °C.
1H NMR (DMSO, 400 MHz): δ = 11.02 (br s, 1H), 8.51 (d,
J = 10.0 Hz, 0.9H, major), 8.36 (d, J = 10.0 Hz, 0.1H, minor),
7.78 (d, J = 8.6 Hz, 0.9H, major), 7.72 (d, J = 8.3 Hz, 0.1H,
minor), 7.63 (t, J = 5.9 Hz, 0.9H, major), 7.61−7.56 (m, 2.1H),
7.42−7.20 (m, 9H), 6.65 (d, J = 10.0 Hz, 0.9H, major), 6.57 (d,
J = 10.0 Hz, 0.1H, minor), 5.41 (s, 2H), 5.04 (s, 1.8H, major),
4.99 (s, 0.2H, minor), 4.44 (d, J = 5.9 Hz, 2H). 13C NMR
(DMSO, 100 MHz): δ = 197.6, 160.7, 156.6, 147.4, 137.4,
137.0, 136.0, 130.2, 128.4, 128.3, 128.0, 127.9, 127.8, 127.6,
125.1, 124.8, 124.2, 117.4, 110.7, 70.0, 65.4, 48.7; HRMS
calculated for C26H23N2O5 (M + H): 443.1601, found:
443.1598. The melting point is 170−172 °C.
Preparation of Benzyl N-[(2R)-2-[8-(Benzyloxy)-2-oxo-1,2-
dihydroquinolin-5-yl]-2-hydroxyethyl]carbamate (2c). To a
300 L glass lined vessel was added degassed HCO2H (17.3 kg,
378.3 mol) under N2 atmosphere. Triethylamine (15.3 kg) was
charged at 6−10 °C for 2 h. (Caution!! Generating gas!) The
resulting solution was evacuated and backfilled with N2 (3
cycles) and aged for 19 h. To the solution was added
compound 1c (6.99 kg, 15.8 mol) and (S,S)-Ms-DENEB
(0.0457 kg, 0.0158 mol) at 13 °C. The resulting slurry was
degassed twice more. The slurry warmed to 50 °C for 1 h and
agitated at 50−54 °C for 6 h until >99.5% conversion was
achieved according to HPLC analysis (Caution!! Vigorous gas
evolution! Refer to HPLC method in the Supporting
Information). To the reaction mixture was charged IPA (41.0
kg) and the seed of compound 2c (ca. 0.1% to the product) at
27−53 °C and the resulting mixture aged at 25 °C for 16 h
until the crystallization was complete. The solid was collected
by filtration and washed twice with cooled IPA (−15 °C, 31.0
kg +14.0 kg). Drying in vacuum at 50 °C afforded compound
2c as a white solid (5.00 kg, 71.2%, 99.7% chemical purity,
98.6% ee).
To the solution of TBS protected compound 2c (<11.3 mol)
was added 2-Me-THF (51.9 kg) and methanol (15.8 kg) under
N2 atmosphere. To the reaction mixture was charged HCO2K
(3.79 kg, 45.2 mol), 5% Pd/C 50% wet (0.50 kg, 0.11 mol), and
AcOH (2.70 kg, 45.2 mol) at 8−10 °C. The slurry was warmed
to 30 °C and aged at 30−36 °C for 4 h until >99.0% conversion
was achieved according to HPLC analysis (refer to the HPLC
method in the Supporting Information). To the slurry of Pd/C
and the desired compound was added deionized water (40.0
kg) and the desired compound was dissolved by stirring at 25−
37 °C for 30 min. The organic layer was separated and filtered
through Celite (3 kg) to remove Pd/C. The filter cake was
washed with 2-Me-THF (16.6 kg) through the line. The
combined filtrate containing the desired compound was
allowed to remain for 16 h under N2 atmosphere below 23
°C. To the solution was added AcOH (1.00 kg, 17.0 mol) and
the seed of (R)-5 (ca. 0.1% to the product) at 31 °C. The
resulting mixture was stirred at 31−35 °C for 1 h to initiate
crystallization. To the slurry was added AcOH in five portions
(0.47 kg + 0.47 kg + 0.47 kg + 0.47 kg + 0.47 kg) every 1 h at
32−35 °C. The resulting mixture was aged for 18 h at 18−33
°C and cooled to 6 °C for 1 h, followed by stirring at 3−6 °C
for 1 h. The solid was collected by filtration and washed with
iPrOAc (36.1 kg). Drying in vacuum at 50 °C afforded (R)-5 as
a white solid (4.25 kg, 83.1%, 99.7% purity, 99.2% ee). The
overall yield was 41.3% over four steps from 1b.
1H NMR (DMSO, 400 MHz): δ = 10.66 (br s, 1H), 8.25 (d,
J = 10.0 Hz, 0.9H, major), 7.93 (d, J = 10.0 Hz, 0.1H, minor),
7.57 (d, J = 7.1 Hz, 2H), 7.43 (t, J = 5.6 Hz, 1H), 7.40−7.00
(m, 10H), 6.55 (d, J = 10.0 Hz, 0.9H, major), 6.20 (d, J = 10.0
Hz, 0.1H, minor), 5.54 (d, J = 4.2 Hz, 1H), 5.28 (s, 2H), 5.10−
4.94 (m, 3H), 3.26−3.18 (m, 1H), 3.09−3.00 (m, 1H). 13C
NMR (DMSO, 100 MHz): δ = 160.9, 156.4, 143.3, 137.2,
136.7, 136.5, 132.2, 129.2, 128.3, 127.9, 127.8, 127.7, 127.6,
122.0, 119.3, 116.8, 112.0, 69.8, 68.1, 65.2, 48.3; HRMS
calculated for C26H25N2O5 (M + H): 445.1758, found:
445.1772. The melting point is 143−145 °C. Residual
ruthenium is 4.1 ppm.
1H NMR (DMSO, 400 MHz): δ = 8.23 (d, J = 10.0 Hz, 1H),
7.88 (br s, 4H), 6.99 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.3 Hz,
1H), 6.50 (d, J = 10.0 Hz, 1H), 5.08 (dd, J = 4.9, 2.2 Hz, 1H),
2.81−2.70 (m, 2H), 1.86 (s, 6H), 0.81 (s, 9H), 0.03 (s, 3H),
−0.19 (s, 3H). 13C NMR (DMSO, 100 MHz): δ = 172.5,
160.7, 143.8, 136.8, 128.8, 128.7, 121.5, 120.5, 116.7, 113.9,
73.1, 49.0, 25.7, 21.7, 17.9, −4.9; HRMS calculated for
D
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(c) Bedore, M. W.; Zaborenko, N.; Jensen, K. F.; Jamison, T. F. Org.
Process Res. Dev. 2010, 14, 432. Abediterol: (d) Marchueta H. I.;
Moyes, V. E. PCT Int. Appl. WO 2013/050375 A1, 2013.
(10) Pivetti, F.; Bocchi, M.; Delcanale, M. PCT Int. Appl. WO 2008/
093188 A1, 2008.
(11) Indacaterol is prepared via epoxide intermediate with low
selectivity, and the diversity of the side chain is subject to restrictions
by the synthetic approach of abediterol. See: ref 9.
(12) We also screened a number of enzymatic agents for preliminary
investigation of the reaction using Codex KRED screening kit
containing 24 ketoreductases that is a commercially available from
Codexis (http://www.codexis.com).
C26H25N2O5 (M + H): 335.1785, found: 335.1774. The
melting point is 140 °C (degradation). Residual ruthenium is
22
not detected. [α]D = −37.7 (c = 2.02, DMSO).
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR, IR, MS, and HPLC spectral data for products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.komiyama@teijin.co.jp.
■
Author Contributions
M.K. and T.I. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Takasago International Corporation
for helpful discussions. We also thank Takasago for the
generous gift of several chiral catalysts.
(13) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.;
Saito, T.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960.
(14) Several solvents such as toluene, CHCl3, i-PrOAc, 2-Me-THF,
1,2-dimethoxyethane, MeCN, DMF, DMSO, water, anisole, and i-
PrOH were investigated. Among them, CHCl3 and anisole gave a
better reaction conversion. Especially, CHCl3 was a preferable solvent
for the ATH.
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dx.doi.org/10.1021/op500338d | Org. Process Res. Dev. XXXX, XXX, XXX−XXX